Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3

Sexual side efects of 5-α-reductase inhibitors fnasteride and dutasteride: A comprehensive review

Raymond M Fertig1, A Caresse Gamret1, Evan Darwin1, Sudeep Gaudi2 Afliations: 1University of Miami, Miller School of Medicine, Department of Dermatology and Cutaneous Surgery, Miami, Florida, 2Pathology and Laboratory Medicine Service, James A Haley VA Hospital, Tampa, Florida Corresponding Author: Raymond Fertig, 1475 NW 12th Ave, 2nd Floor Miami Florida, 33136, Email: [email protected]

Abstract doses, with increasing of label use for androgenetic alopecia [4-6]. Additionally, these drugs are under The 5-α-reductase inhibitors fnasteride and study for their use in prevention of prostate cancer dutasteride are frequently used in the treatment [7]. Dihydrotestosterone has been found to be the of androgenetic alopecia and benign prostatic primary androgen involved in the pathogenesis hyperplasia. These drugs are efective at reducing of androgenetic alopecia by promoting follicular levels of dihydrotestosterone, the primary androgen miniaturization [8], as well as, in the pathogenesis responsible for the pathogenesis of both these of BPH, by preventing the growth of epithelial conditions. However, fnasteride and dutasteride cells in the prostate [9, 10]. Finasteride reduces have also been shown to produce an increase in the dihydrotestosterone (DHT) levels by up to 70% in incidence of sexual dysfunction, namely, impotence, both the serum and the scalp skin at the 5 mg/d dose decreased libido, and ejaculation disorder. The [11, 12], with DHT reduction being dose dependent. purpose of this study is to review the existing medical Dutasteride 0.5 mg/d can reduce DHT serum levels literature with regard to the sexual side efects of by upwards of 90%, again in a dose dependent 5-α-reductase inhibitor therapy. This review is an manner [13]. Although both of these drugs have extensive look at the sexual efects of 5-α-reductase been proven efective at reducing male pattern hair inhibitors and compares outcomes for fnasteride loss and BPH through the reduction of DHT levels, versus dutasteride in addition to comparing sexual there has been debate over the adverse sexual side side efects for each of the diferent dosages efects they produce [14, 15]. These side efects prescribed of fnasteride and dutasteride. include decreased ejaculate volume, reduced libido, ejaculatory dysfunction, and erectile dysfunction Keywords: dutasteride, fnasteride, sexual side efects, [16]. As these 5αRIs are taken by more than 30 million sexual dysfunction, depression, androgenetic alopecia, men, even the infrequent incidence of sexual adverse benign prostatic hyperplasia, 5-α-reductase inhibitors efects could have a profound efect on the sexual satisfaction and quality of life, of a large population [10]. This review will assess the fndings regarding the Introduction sexual side efects of fnasteride and dutasteride in Finasteride and dutasteride are 5-α-reductase the current literature. inhibitors which prevent the conversion of testosterone to dihydrotestosterone via the enzyme Body of Article 5-α-reductase. Finasteride is a type I 5-α-reductase inhibitor (5αRI) prescribed in 1 mg and 5 mg doses to Materials and Methods treat male pattern androgenetic alopecia (AGA) and A PubMed search (1950 to 2017) identifed benign prostatic hyperplasia (BPH), [1-3]. Dutasteride documented cases of fnasteride and dutasteride is also a competitive inhibitor of this enzyme, sexual side efects in the literature. The search terms targeting both type I and II 5-α-reductase and is used were: “fnasteride side efects,” “fnasteride used to treat benign prostatic hyperplasia at 0.5 mg side*,” “fnasteride sexual,” “fnasteride sexual side

- 1 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 efects,” “fnasteride sexual dysfunction,” “fnasteride 6. High probability of publication bias. depression,” “fnasteride suicidal ideation,” “fnasteride side efects alopecia,” “fnasteride Sexual Adverse Efects syndrome,” “post-fnasteride syndrome,” “dutasteride Sexual side efects in men who have taken side efects,” “dutasteride side*,” “dutasteride sexual,” fnasteride (1mg, 5mg) and dutasteride (0.5mg) are “dutasteride sexual side efects,” “dutasteride sexual well documented and include decreased libido, dysfunction,” “dutasteride depression,” “dutasteride erectile dysfunction, and ejaculatory dysfunction. suicidal ideation,” “dutasteride side efects alopecia.” Randomized clinical trials have demonstrated Clinical trials, review articles, case series, and case increased incidences of these sexual side efects and reports that mentioned fnasteride and dutasteride are summarized in Tables 1 and 2. sexual side efects were included. In addition to our PubMed searches, we examined the references of Finasteride 5mg included sources to add any cases which may have The Prostate Cancer Prevention Trial (PCPT) was been initially omitted. a randomized, double-blind, placebo-controlled study that provided an opportunity to prospectively Using the American College of Physicians outcome study the efects of f nasteride (5 mg/d) and other study grading system each studies’ level of evidence covariates on sexual dysfunction [15]. Sexual was ranked from high to very low. This system rates dysfunction in 17,313 PCPT participants was assessed quality of studies in accordance with the underlying during a 7 year period. Questionnaires assessed methodology in four categories: sexual dysfunction using the Sexual Activity Scale score, with scores ranging from 0 to 100 (higher 1. High, including randomized trials or double- numbers correlate with greater sexual dysfunction). upgraded observational studies. Confounding variables analyzed included age, physical function and vitality scores, body mass 2. Moderate, including downgraded randomized index, smoking status, and the presence of diabetes trials or upgraded observational studies. and hypertension. Assessments began at month 6 and continued during the 7 year trial period. Trial 3. Low, including double-downgraded randomized results concluded that fnasteride increased sexual trials or observational studies. dysfunction only slightly and its impact diminished over time [17]. Finasteride users showed a statistically 4. Very low, including triple-downgraded randomized signifcant increase in the Sexual Activity Scale score trials or downgraded observational studies or case relative to placebo of 3.21 points (P < 0.001) at the series/case reports. frst assessment conducted at the 6 month mark. This increase in scale score persisted throughout Studies can be downgraded in presence of factors the study but decreased to 2.11 points (P <0.001) that may decrease the quality level of a body of relative to placebo at study end [15]. Importantly, evidence. These include: other covariates in this study population including diabetes, hypertension, smoking, declining physical 1. Limitations in the design and implementation of function, and increased BMI were found to have a available studies suggesting high likelihood of bias. similar detrimental efect on sexual dysfunction, with age demonstrating a greater efect on sexual 2. Indirectness of evidence (indirect population, dysfunction than fnasteride [18]. Persistent sexual intervention, control, outcomes). side efects were not reported in any of the 17,313 study participants [18]. Sexual side efects were more 3. Unexplained heterogeneity or inconsistency of commonly reported with fnasteride at some time results (including problems with subgroup analysis). during the study and included decreased ejaculate volume, erectile dysfunction, and loss of libido [19]. 4. Imprecision of results (wide confdence intervals). However, based on this covariate analysis, the authors concluded fnasteride has a minimal efect on sexual

- 2 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 function for most men that decreases with time and Prostatic Symptoms) study, the long term efects of that this fnding should not afect the decision to fnasteride (5 mg/d) and doxazosin (an α-adrenergic prescribe fnasteride for patients [15]. receptor blocker used to treat BPH) were compared to placebo over 4 years [22]. The MTOPS study was In the PROWESS 2-year multicenter, double-blinded, a multicenter, randomized, double-blind, placebo- placebo-controlled study, the long term efects of controlled clinical trial. Sexual function was assessed fnasteride (5 mg/d) were examined for men aged 50 with the Brief Male Sexual Function Inventory, an 11 to 75 with moderate BPH. Of the 3,168 participants, item questionnaire to determine functional aspects any sexual adverse event, including a change in and satisfaction with sexuality in the last 30 days [23]. libido, ejaculation disorder, impotence, or orgasm There were 695 in the fnasteride group and 672 in the dysfunction, was reported in 10% of the fnasteride placebo group, both with a mean age of 62 years old. group versus 7% in the placebo group [20]. Decreased In the fnasteride group compared to baseline, after libido, ejaculation disorder, and impotence were 1 year 16% of men showed worse sexual function, reported in 4, 2.1, and 6.6%, respectively in the 11% showed worse erectile function, 9% showed fnasteride group, compared to 2.8, 0.6, and 4.7% worse ejaculatory function, and 15% showed worse for the control group. Only ejaculation disorder and overall sexual satisfaction (placebo showed 11%, 8%, impotence were found to be statistically signifcant 6%, and 14%, respectively). Of these fndings, only diferences between the groups (P <0.05). The worsened sexual drive was a statistically signifcant discontinuation rate was the same for both the diference (P <0.0167). After 4 years, 22% had worse fnasteride and placebo groups (1%). These sexual sexual drive, 18% had worse erectile function, side efects were considered to be drug related by the 18% had worse ejaculatory function, and 21% had investigators. However, they still consider fnasteride worse overall sexual satisfaction (placebo had 16%, a well-tolerated and efective long term treatment 13%, 12%, and 17%, respectively), with both sexual for BPH [20]. drive and ejaculatory function being signifcant (P <0.0167) [22]. Fwu et al. suggest that the impact Another study comparing the long-term efects of of fnasteride on sexual function is undervalued by fnasteride (5 mg/d) and placebo in patients with physicians and that the potential for long term sexual BPH was the Finasteride Long-Term Efcacy and side efects should be discussed with patients prior Safety Study Group [21]. In this 4-year double-blind, to prescribing. randomized, placebo-controlled trial, complete data were available for 2,070 subjects. Adverse events In the Scandinavian BPH Study Group’s 2-year, related to sexual dysfunction were found to be multicenter, double-blind comparison between signifcantly higher in the fnasteride arm compared to fnasteride 5 mg/d and placebo, sexual dysfunction the placebo arm (decreased libido 6.4% versus 3.4%; was 19% and 10%, respectively (P <0.01), [24]. The impotence 8.1% v versus 3.7%; decreased ejaculate PROSPECT study compared the long-term efects volume 3.7% versus 0.8%; ejaculation disorder 0.8% of fnasteride (5 mg/d) and placebo in patients with versus 0.1%) [21]. However, the decreased libido moderate BPH [25]. A total of 472 subjects were and impotence diferences existed only in year one followed in this 2-year double-blind, randomized, of the study. In years 2-4 of the study, there was placebo-controlled, multicenter study. The incidence no diference in decreased libido and impotence of adverse events related to sexual dysfunction were in the fnasteride group and the placebo group found to be signifcantly higher in the fnasteride arm (decreased libido 2.6% both groups, impotence 5.1% compared to the placebo arm (ejaculation disorder both groups). In addition, in years 2-4 there was no 7.7% versus 1.7% and impotence 15.8% versus 6.3%, statistical diference in ejaculation disorder between P <0.01), [25]. the groups. However, a small statistically signifcant diference of greater incidences of decreased In another study looking at the long term efects ejaculate volume remained in the fnasteride group. of fnasteride (5 mg/d), 190 men were followed for a 6 month double-blind, placebo-controlled study In the Fwu analysis of the MTOPS (Medical Therapy of of fnasteride with an open-label extension of 7

- 3 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 to 8 years. The fndings show that that impotence, placebo-controlled study 4 men in the 5mg group decreased libido, and ejaculation disorder were the withdrew due to sexual side efects, 3 in the 1 mg most common drug related adverse events. However, group, and 1 in the placebo group. At the study’s only 0-1.9% (0% during the double-blind phase and close, Gormley et al. suggest that 5mg fnasteride is years 4-8, and 1.9% in year 1) of subjects discontinued the recommended dose to efectively treat BPH and the study in any given year owing to these sexual side that any dose of fnasteride is associated with an efects [26]. During the initial 6 month study phase increased likelihood of sexual dysfunction [28]. there were no cases of sexual adverse efects reported among the placebo group (0%) compared to 0.7% In a study by Roberts et al. regarding fnasteride impotence and decreased libido for the fnasteride dosing, specifcally for the treatment of androgenetic group. Following this period into the open label alopecia, daily doses of fnasteride 5mg, 1mg, 0.2mg, extension, the frst year had by far the most reports of and 0.01mg were compared in 18 to 36-year-olds side efects (10.9% decreased libido, 5.8% ejaculation [29]. In the multicenter, randomized, double blinded, disorder, 6.4% impotence), with subsequent years placebo-controlled clinical study it was determined having fewer new incidences (year 2: 2.5% decreased that all doses equal to or greater than 0.2mg were libido, 0.8% ejaculation disorder, 2.5% impotence; efcacious and that 1mg was the ideal dose to treat year 3: 2% decreased libido, 1% ejaculation disorder, male pattern hair loss. At the 6 month point, after 1% impotence; falling to 0% in all categories by year which a non-placebo controlled voluntary extension 8), [26]. Again, the authors concluded fnasteride was ofered, incidences of any sexual adverse was efective and well tolerated and recommended efects, decreased libido, and erectile dysfunction it for long term treatment of benign prostatic were measured for each of the doses and placebo hyperplasia. In the Wilton et al. observational cohort (5mg: 3.6%, 2.7%, 1.8%, respectively; 1mg: 4.3%, study involving 14,772 subjects taking fnasteride 5 1.7%, 2.6%, respectively; placebo: 3.4%, 3.0%, 0%, mg/d for BPH, impotence, or ejaculatory failure was respectively), [29]. None of these diferences were reported in 2.1% of subjects and decreased libido in considered signifcant. Another androgenetic 1% of subjects [27]. alopecia fnasteride dosing study by Drake et al. compared daily doses of 0.01mg, 0.05mg, 0.2mg, Finasteride 5mg versus 1mg 1mg, and 5mg to placebo [11]. Among the group The Finasteride Study Group compared the efects of of 249 men included in the double-blind, placebo- fnasteride 5 mg/d versus fnasteride 1 mg/d versus controlled study, only headache and decreased libido placebo in 895 men aged 40 to 83 years old who were reported by more than 1 patient in any group. had a low urinary fow rate (less than 15 ml/sec), Placebo reported 4.5% incidence of decreased libido, an enlarged prostate gland on digital rectal exam, compared to 0% for the 1mg fnasteride group, and and the diagnosis of BPH. Of the 295 men in the 2.6% for the 5mg group [11]. 5mg fnasteride group 4.7% experienced decreased libido, 4.4% experienced ejaculatory disorder, 3.4% Finasteride 1mg experienced impotence, and 0.7% experienced The Finasteride Male Pattern Hair Loss Study orgasm dysfunction. In the 1mg treatment group, conducted two replicate, 1-year, double-blind, of 298 patients, 6% had decreased libido, 4.4% had placebo-controlled, randomized studies in 1,553 ejaculatory disorder, 5% had impotence, and 0.3% men (age 18 to 41) with male pattern hair loss who had orgasm disorder (compared to 1.3%, 1.7%, 1.7%, received oral fnasteride 1 mg or placebo [30]. In the and 0.3% for placebo group, respectively, n=300), [28]. frst year, a higher proportion of fnasteride-treated Decreased libido and ejaculatory volume were found patients reported adverse events related to sexual to be statistically signifcant fndings for both the function (4.2% versus 2.2% control arm, P <0.05), 5mg and 1mg fnasteride treatments groups versus [30]. Only 11 men (1.4%) in the fnasteride group the placebo (P <0.05). Impotence was also found and 8 (1.0%) in the placebo group discontinued the to be signifcantly higher for the 1 mg treatment study because of sexual adverse events. The sexual group compared to placebo (P <0.05), [28]. During side efects resolved after fnasteride therapy was the course of this 1 year, double-blind, randomized, discontinued. After one year, 1,215 men continued

- 4 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 in blinded 1-year extension studies for a second year. Cancer Events) trial, a 4-year, multicenter, randomized, In the extension studies, patients were randomly double-blind, placebo-controlled study involving assigned treatment to either fnasteride 1 mg or 6,729 men, compared dutasteride 0.5 mg daily to placebo. Finasteride resulted in slightly more sexual placebo. There were 3,305 subjects in the dutasteride side efects compared to placebo, with the incidence group and 3,424 in the placebo group. Erectile of erectile dysfunction, decreased ejaculatory dysfunction was reported in 9.0% of the subjects in volume and decreased libido being higher in the the dutasteride group and in 5.7% of the subjects in fnasteride group (1.4%, 1.0%, 1.9%, respectively) the placebo group (P <0.001), [34]. Moreover, 3.3% compared with the control group (0.9%, 0.4%, 1.3%, of the subjects in the dutasteride group experienced respectively), [30]. a decrease in libido as compared with 1.6% of the subjects in the placebo group (P <0.001), [34]. In a 48 week randomized, double-blind study of Upon comparison of dutasteride 0.5mg to placebo, fnasteride treatment of androgenetic alopecia, Roehrborn et al. found dutasteride was associated efcacy of 1mg and 0.2mg fnasteride were compared with a signifcant increase in impotence, decreased in 414 men. The incidence of decreased libido was libido, and ejaculation disorder compared to placebo 2.9%, 1.5% and 2.2% for fnasteride 1mg, 0.2mg, (dutasteride: 7.3%, 4.2%, and 2.2%, respectively, and placebo, respectively [31]. Most of these cases placebo: 4%, 2.1%, 0.8%, respectively, P <0.001) resolved during the course of therapy and there during the frst year of this 2 year, randomized, were no discontinuations of the study related to the double-blind study (N=4,325), [35]. During the adverse drug efects [31]. second year, there were no signifcant diferences between the two groups. An additional study conducted by Leyden et al. was a one-year, double-blind, placebo-controlled, Erectile dysfunction and decreased libido have also randomized study in 326 men with male pattern hair been reported in the CombAT trial, a double-blind, loss who received oral fnasteride 1 mg/d or placebo randomized, placebo controlled trial evaluating the followed by a one-year extension study [32]. The only efcacy of dutasteride in treating BPH [36]. In this trial, drug-related adverse efects were sexual adverse 1,623 subjects were treated with dutasteride (0.5mg) efects, reported in approximately 2% of men in both for BPH whereas 1,611 subjects were treated with the treatment groups, with 2 patients in each treatment alpha blocker tamsulosin (placebo). In a 4-year follow- group reporting decreased libido and 1 patient in the up analysis, Roehrborn et al. reported that 7% of the fnasteride-treatment group reporting impotence patients treated with dutasteride reported erectile [32]. No patients discontinued the study because of dysfunction compared to 5% of subjects treated with sexual adverse side efects. In the study extension tamsulosin [37]. Furthermore, 3% of the patients period, there was no increase in any drug-related treated with dutasteride reported decreased libido adverse experiences. The Merck-sponsored Van Neste compared to 2% in the tamsulosin group [37]. Eun et al. multicenter 48-week, randomized, double- et al. completed a similar phase III study comparing blind, placebo-controlled study also looked at the 0.5 mg/d dutasteride to placebo for the treatment efect of 1 mg/d fnasteride in 212 men with AGA, of male pattern hair loss. The 6 month multicenter, aged 18 to 40 years. They reported that 1.9% of the double-blind, placebo controlled trial included 148 fnasteride 1mg treatment group experienced sexual men aged 18 to 49 years (38). Assessment of sexual adverse events compared to 0.9% in the placebo function utilized a problem assessment domain to group. There were no discontinuations of the study determine perception of lack of sex drive, ability to related to adverse efects [33]. Of the two men who obtain and maintain erections, and ejaculation. In the reported sexual adverse events one had resolution 0.5mg dutasteride group, 4.1% experienced sexual during therapy and the other had resolution two dysfunction compared to 2.7% of the placebo group. weeks after therapy ended [33]. These fndings were not statistically signifcant [38].

Dutasteride 0.5mg In the Japanese BPH study by Tsukamoto et al., The REDUCE (Reduction by Dutasteride of Prostate 0.5mg dutasteride (n=70) was compared to placebo

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(n=66). Performed at 26 centers in Japan, this 1-year, fnasteride 5mg after 24 weeks (P =0.026), [13]. randomized, double-blind, placebo-controlled Dutasteride 2.5mg was also shown to be signifcantly study found that in men 50 years or older with BPH, more efective than dutasteride 0.5mg at increasing erectile dysfunction occurred in 4% of subjects hair growth. Rates of decreased libido, ejaculation taking dutasteride [6]. There were no cases of erectile disorders, and impotence were 13%, 1%, and 0% for dysfunction in the placebo group. The incidence dutasteride 2.5mg, respectively; 1%, 1%, and 0% for of sexual dysfunction while taking dutasteride dutasteride 0.5mg, respectively; 4%, 3%, and 1% for 0.5mg was considered infrequent and the drug was fnasteride 5mg, respectively; and 3%, 0%, and 5% recommended for treatment of BPH owing to its for placebo, respectively [13]. Of the 13% of subjects efectiveness. who reported decreased libido in the dutasteride 2.5mg treatment group, 4 resolved during treatment, Finasteride versus Dutasteride 1 within 3 weeks of stopping therapy, and 1 within A study comparing the safety profle of dutasteride 8 weeks of stopping; 1 patient had decreased libido (0.5 mg/d) and fnasteride (5 mg/d) for treating BPH that persisted after stopping but was considered by was performed by Andriole et al. In the dutasteride the patient to be unrelated to the drug [13]. Based group of 813 subjects, impotence occurred in 7%, on these fndings the authors suggest that while decreased libido in 5%, and ejaculation disorder in dutasteride 0.5mg is the recommended daily dose for 1%. Impotence was experienced by 8%, decreased BPH (this drug is not FDA approved for androgenetic libido by 6%, and ejaculation disorder by 1% in the alopecia but it is prescribed for such as an of label fnasteride 5mg group (n=817), [5]. These diferences use), dutasteride 2.5mg is signifcantly more efective were not considered signifcant and the safety profle at reducing DHT levels and thus could have a greater of dutasteride was considered no diferent than therapeutic impact at these levels. fnasteride by the authors based on their parallel group, comparator trial. Finally, Kaplan et al. conducted a retrospective analysis of 378 consecutive men treated at a single The Gubelin Harcha et al, 2014 multicenter, clinic with 5α-reductase inhibitor monotherapy for randomized, double-blind, placebo-controlled study lower urinary tract symptoms related to BPH [40]. also compared dutasteride (0.02, 0.1, or 0.5mg), Treatment duration was fve years. Of those enrolled, fnasteride (1mg), and placebo in the treatment of 197 subjects were treated with fnasteride (5 mg) androgenetic alopecia for 917 men (20-50 years and 211 with dutasteride (0.5 mg). At 5 years, 57.4% old). Dutasteride 0.5mg was found to signifcantly of men in the fnasteride group and 42.5% of men increase hair growth compared to fnasteride 1mg in the dutasteride group remained on treatment. and placebo with a similar rate of adverse side efects. Dutasteride resulted in more sexual side efects Altered libido, impotence, and ejaculation disorders leading to discontinuation compared to fnasteride, were listed for all groups (dutasteride 0.5mg: 4.9%, with the incidence of erectile dysfunction, ejaculatory 5.4%, and 3.3%, respectively; fnasteride 1mg: 6.7%, dysfunction, and decreased libido being signifcantly 6.1%, 3.9%, respectively; placebo: 1.7%, 3.9%, 3.3%, higher in the dutasteride group (5.1%, 2.4%, 2.7%, respectively), [39]. There was no signifcant diference respectively) compared with the fnasteride group found between fnasteride and dutasteride sexual side (2.1%, 1.8%, 1.4%, respectively) [40]. Of those subjects efects and additionally, a dose dependent response who remained on treatment for fve years, dutasteride of sexual side efects for any of the treatment doses resulted in signifcantly greater erectile dysfunction of dutasteride was absent [39]. Sexual side efects than fnasteride. At year 5, subjects on dutasteride were found to decrease over time. therapy had signifcantly worsened International Index of Erectile Function scores relative to baseline In the Olsen et al. androgenetic alopecia study than did those on fnasteride [40]. This suggests that comparing multiple doses of dutasteride (0.05mg, dutasteride may have stronger negative adverse 0.1mg, 0.5mg, 2.5mg) versus fnasteride 5mg, sexual efects compared to fnasteride. dutasteride 0.5 mg was shown to be signifcantly superior at promoting hair growth compared to Finasteride Persistent Side Efects

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Although the potential for adverse sexual side found that 89% still had sexual dysfunction [45]. This efects has been adequately demonstrated by the raises the possibility of permanent efects related to previously discussed studies, none to this point have fnasteride in a small portion of patients. shown that the efects have lasted more than a few weeks after stopping drug therapy. The Proscar Long- Depression and Sexual Side Efects Term Efcacy and Safety Study (PLESS) examined These long lasting side efects, albeit infrequent, just this, the incidence of persistent sexual adverse leads one to ponder the mechanism via which sexual experiences in 3,040 men between the ages of 45 dysfunction persists. Basaria et al. strived to answer and 78 years old with BPH. The study was a 4 year, this very question in their systematic evaluation of double-blind, randomized, placebo-controlled 56 men who had previously used fnasteride (1 mg) attempt to ascertain the efcacy and safety profle and were experiencing persistent sexual side efects of fnasteride 5mg/d [41]. Researchers found that (n=25), men who had previously used fnasteride (1 15% of subjects in the fnasteride group experience mg) with no persistent sexual side efects (n=13), or sexual side efects in the frst year compared to 7% in a control group who had neither used fnasteride the placebo group (P <0.001), [42]. In the remaining nor had sexual dysfunction (n=18), [46]. It was found years of the study there was no diference between that in the persistent side efects group there was groups (7% for both). The sexual side efects cleared not androgen defciency, androgen insensitivity, nor during therapy for 12% and 19% of those in the lasting inhibition of steroid 5α-reductase. There was, fnasteride and placebo groups, respectively. The however, depressed mood, negative afect, and neural discontinuation rate related to sexual adverse circuitry in these men that has been associated with efects was 4% for fnasteride and 2% for placebo; major depression, as seen on fMRIs (P <0.001), [45, however, only 50% and 41% experience resolution of 46]. Therefore, the authors concluded that treatment their sexual symptoms after discontinuing therapy, for persistent sexual dysfunction in this group should respectively [42]. The study concluded that only target the depression and sexual symptoms rather during the frst year was fnasteride associated with than utilize androgen based therapies [46]. This a higher incidence of sexual adverse events and link between depression and sexual dysfunction that the likelihood of sexual side efects was not suggests that 5αRIs may lead to sexual dysfunction related to pre-existing sexual dysfunction in men. both directly and indirectly through depression and Half of the population that discontinued owing to prompted us to delve further into the relationship. sexual side efects experienced persistent sexual All studies on the subject have been summarized in dysfunction, which is typical of the natural history Table 3. of sexual dysfunction in the patient population [42, 43]. Irwig and Kolukula also sought to determine the Neurosteroids and related compounds are prevalence of persisting sexual side efects following hormones that have been shown to be active the use of fnasteride 1mg/d to treat male pattern in the central nervous system. Among the hair loss in two uncontrolled studies, graded very low compounds that are active are pregnenolone, by the ACP outcome system. In one they interviewed allopregnanolone, dihydrodeoxycorticosterone, and 71 men (21-46 years old) who experience sexual side dehydroepiandrosterone, among others [47]. These efects following the discontinuation of fnasteride compounds are thought to have neuroprotective for at least 3 months (patients were recruited from efects, namely they are considered antidepressant, Irwig’s clinic and the website propeciahlep.com). anxiolytic, and memory enhancing [47, 48]. Subjects used fnasteride for an average of 28 months Depression has been shown to be related to both and sexual side efects persisted for an average of 40 androgen defciency and the dysregulation of these months at the time of interview. Of those interviewed, neurosteroids [49, 50]. 5αRIs are thought to decrease 94% reported low libido, 92% reported erectile synthesis of these neurosteroids and may lead to dysfunction, 92% reported decreased arousal, and psychological efects in addition to sexual efects via 69% had difculty with orgasm [44]. In the following this mechanism [51]. study by Irwig, he reassessed the sexual function of 54 of the original participants after 14 months and Welk et al. performed a retrospective, cohort study

- 7 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 with 93,197 matched pairs; men aged 66 or older who sexual dysfunction (reduced libido or reduced had taken fnasteride (52%) or dutasteride (48%) for ejaculate volume) in addition to the depression. BPH were matched to men of a similar profle who were These drug induced mood afects resolved within 3 not taking 5αRIs. The study purpose was to measure days to 3 months after drug cessation [54]. incidents of suicide, self-harm, or depression among those taking these drugs compared to controls. It In Rahimi-Ardabili et al’s prospective study of 128 was found that there was not a signifcant increase men (average age 25.8) who used fnasteride (1 in the rate of suicide for those taking 5αRIs versus mg/d) for AGA, there was found to be a minimal but control (HR 0.88, 95% CI = 0.53-1.45) [52]. However, signifcant increase in depression after fnasteride there was a signifcant increase in both the risk for treatment as compared to before [55]. Depression self-harm and depression. Self-harm was found to be was assessed before and after treatment using increased in the drug group for the frst 18 months both the Beck Depression Inventory (BDI) and of therapy (HR 1.88, 95% CI = 1.34-2.64), but after Hospital Anxiety and Depression Scale (HADS). The that there was no diference compared to the control Beck Depression Inventory showed an increase in group. Depression on the other hand was found to be depression of 0.69 points (P <0.001). HADS showed elevated both in the frst 18 months of drug therapy a signifcant increase in depression of 0.57 points (HR 1.94, 95% CI = 1.73-2.16) and thereafter, but to a and an increase in anxiety that did not prove to be lesser extent (HR 1.22, 95% CI = 1.08-1.37), [51, 52]. signifcant. In addition, transient loss of libido was There was not a marked diference in these results for found in 9.4% of subjects. However, there was not fnasteride compared to dutasteride. a signifcant diference in either BDI or HADS in this subset [55]. A multicenter, prospective, longitudinal case control clinical trial was performed by Melcangi et al. that Another study, by Ali et al., utilized the FAERS adverse measured neuroactive steroids in cerebrospinal drug event database and Multi-item Gamma Poisson fuid (CSF) and plasma, peripheral neuropathy, and Shrinker analysis to determine rates of sexual depression in 16 men with persistent side efects dysfunction and suicidal ideation post fnasteride following fnasteride 1mg treatment (they had 1mg use for androgenetic alopecia. There were 4,910 discontinued use for a median of 5.4 years) compared FAERS reports from 1998 to 2013 for men 18 to 45 to 25 healthy controls [53]. It was found that of the years old. Of these reports 11.8% of them were for treatment group 14 out of 16 (87.5%) had abnormal persistent sexual dysfunction and 0.79% were for CSF and plasma neuroactive steroids (the normal suicidal ideation [56]. Of those reports of suicidal levels were ascertained from the 25 control subjects). ideation, 87% also reported sexual dysfunction. On Additionally, 50% of the persistent fnasteride side average, these men experienced sexual dysfunction efects group demonstrated major depression and for 5.4 months after stopping fnasteride use and 25% had peripheral neuropathy of the pudendal suicidal ideation for 2.4 years among those who had nerve. Severe erectile dysfunction was present in both suicidal ideation and sexual dysfunction [56]. 62.5% of the fnasteride group and 100% of this Although causality cannot be established based group showed some level of ED [53]. on these fndings Ali et al. propose a mechanistic relationship between low dose fnasteride use, In a retrospective case series looking at 19 patients sexual dysfunction, and suicidal ideation. Finasteride (14 men and 5 women) by Altomare and Capella, inhibits 5-α-reductase, which serves to decrease DHT moderate to severe depression was looked at during levels. This androgen is implicated in both sexual the course of AGA treatment with fnasteride 1mg. function and central nervous system neurosteroids Within one month of starting fnasteride drug therapy that modulate both depression and anxiety [56]. all 19 of these patients developed mood disturbances [54]. Interestingly, 13 of these patients developed Caruso et al. performed a case-control study depressive symptoms despite reporting that the comparing 7 AGA post fnasteride (1-1.25 mg/d) treatment seemed efective at stabilizing hair loss. Of patients versus 12 healthy controls. These post the men in the study, 4 of them reported developing fnasteride patients (average age 38 years old) are

- 8 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 characterized as having experienced lasting sexual who were experiencing these long term adverse side efects and depression or anxiety after stopping drug efects had a psychiatric diagnosis prior to drug therapy (time since therapy ranged from 171- starting therapy and 28.8% had a frst degree relative 5000 days), [57]. Among the 7 in the post fnasteride with such a diagnosis. The authors thus concluded treatment group, depression was reported in 86%, that preexisting psychological disorders or a family loss of libido in 86%, and erectile dysfunction in 71%. history of such could indicate a vulnerability, which Lumbar punctures were performed on all subjects. fnasteride therapy serves to exacerbate and this has The CSF and plasma fndings, somewhat beyond the led to persistent efects among this population [60]. scope of this paper, showed decreased levels of T The authors advise taking a thorough mental health metabolite and PROG levels during therapy as well as history on both the individual and family members persistently altered neurosteroid levels (PREG, PROG, prior to initiating therapy [60]. DHP, THP T, DHT, among others) associated with symptoms of depression and sexual difculties [57]. Meta-Analysis In addition to the aforementioned studies, the meta- Irwig also examined rates of depression among analysis by Liu et al. pooled 17,494 subjects from 17 men with persistent sexual side efects following randomized control trials to determine the relative fnasteride (1 mg/d) AGA treatment. It was found that risk of sexual dysfunction, erectile dysfunction, and among the 61 men recruited from propeciahelp.com decreased libido in those taking 5αRIs for benign and his personal practice sufering from persistent prostatic hyperplasia and androgenetic alopecia [10]. sexual dysfunction that rates of depression were Of the studies included, 9 evaluated the efcacy of signifcantly higher for these men compared to the 5αRIs for BPH whereas 8 assessed their efcacy for control group of 29 men recruited from the local AGA. For men with BPH the relative risk of sexual community (the control group sufered from AGA but dysfunction was 2.56 (95% CI = 1.48-4.42). The had never taken fnasteride), [58]. Rates of depression, relative risk of sexual dysfunction for AGA was 1.21 as assessed by the Beck Depressive Inventory II, were (95% CI = 0.85-1.72). Erectile dysfunction relative risk 75% versus 10% for treatment and control groups, for BPH was 1.55 (95% CI = 1.14-2.12) and for AGA respectively (P <0.0001). Suicidal ideation was also it was 0.66 (95% CI = 0.20-2.25). Finally, the relative reported in 44% of the fnasteride group compared risk for decreased libido was 1.69 (95% CI = 1.03-2.79) to 3% of controls (P <0.0001), [58]. in those with BPH, compared to 1.16 (95% CI = 0.50- 2.72) for AGA [10]. Based on the Liu et al. analysis, it An internet survey was utilized by Ganzer et was concluded that there is a signifcantly increased al. to characterize the symptoms experienced incidence of adverse sexual efects in men who take by men with persistent side efects following 5-α-reductase inhibitors (fnasteride and dutasteride) fnasteride 1mg treatment of AGA (recruitment for the treatment of BPH compared to placebo. was via Propeciahelp.com). The goal was to assess However, there is not a signifcant increase in sexual the prevalence and characteristics of cognitive, adverse efects in men who take these drugs for psychological, and physical efects among 131 the treatment of male pattern hair loss. Something patients with a mean age of 24 years [59]. Among that should be taken into consideration with this the symptoms reported were: decreased sex drive distinction is that BPH is common among men over (93%), complete loss of sex drive (63%), intermittent the age of 50 and BPH is typically treated with higher erectile dysfunction (83%), complete impotence doses of 5αRIs than AGA. This may suggest that the (40%), diminished semen volume and force (82%), association between BPH treatment and sexual depressed afect (73%), and suicidal ideation (63%), dysfunction could be at least partially related to drug [59]. A subsequent study by Ganzer and Jacobs, dosage and older age [10]. Erectile dysfunction was meant to expand upon the previous one, assessed found to be the most common sexual side efect the association between preexisting conditions or among those taking various doses of fnasteride or family history of psychological disorders and the dutasteride [10, 60]. vulnerability for developing persistent fnasteride side efects [60]. It was found that 55% of subjects Interestingly, it was found in subgroup analyses that

- 9 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 for the treatment of BPH dutasteride (RR = 4.09, 95% References CI = 1.03-16.31) has a signifcantly higher relative risk 1. Sinclair R. Male pattern androgenetic alopecia. BMJ. 1998;317(7162):865-9. [PMID: 9748188]. of sexual adverse efects compared to fnasteride (RR 2. McVary KT, Roehrborn CG, Avins AL, Barry MJ, Bruskewitz RC, = 1.54, 95% CI = 1.02-2.32), [10]. The same was not true Donnell RF, Foster HE, Jr., Gonzalez CM, Kaplan SA, Penson DF, for the treatment of AGA. For those treated for male Ulchaker JC, Wei JT. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011;185(5):1793-803. Epub pattern hair loss, the relative risk for each treatment 2011/03/23. [PMID: 21420124]. was compared. The RRs of sexual side efects were 3. Tsuboi R, Itami S, Inui S, Ueki R, Katsuoka K, Kurata S, Kono T, Saito 1.12 (95% CI = 0.63-1.99) for fnasteride 5 mg/d, 0.87 N, Manabe M, Yamazaki M. Guidelines for the management of androgenetic alopecia (2010). J Dermatol. 2012;39(2):113-20. Epub (CI = 0.54-1.39) for fnasteride 1 mg/d, 0.43 (95% CI 2011/12/17. [PMID: 22171995]. = 0.22-0.87) for dutasteride 0.5 mg/d, and 1.40 (95% 4. Arif T, Dorjay K, Adil M, Sami M. Dutasteride in Androgenetic CI = 0.72-2.71) for 0.1 mg/d. However, none of these Alopecia: An Update. Curr Clin Pharmacol. 2017;12(1):31-5. Epub 2017/03/16. [PMID: 28294070]. fndings had a P value of less than 0.3, indicating a 5. Andriole GL, Kirby R. Safety and tolerability of the dual 5alpha- lack of signifcance [10]. Finally, in the treatment of reductase inhibitor dutasteride in the treatment of benign BPH, it was found that there is an increased risk of prostatic hyperplasia. Eur Urol. 2003;44(1):82-8. Epub 2003/06/20. [PMID: 12814679]. sexual adverse efects for men taking fnasteride 5 6. Tsukamoto T, Endo Y, Narita M. Efcacy and safety of dutasteride mg/d or dutasteride 0.5 mg/d for longer than a year in Japanese men with benign prostatic hyperplasia. Int J Urol. compared to treatment durations for less than a year 2009;16(9):745-50. Epub 2009/08/14. [PMID: 19674165]. 7. Canguven O, Burnett AL. The efect of 5 alpha-reductase inhibitors [10]. on erectile function. J Androl. 2008;29(5):514-23. Epub 2008/04/19. [PMID: 18421068]. Conclusion 8. Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol. 2002;198(1-2):89-95. Epub 2003/02/08. [PMID: 12573818]. Although the 5αRIs fnasteride and dutasteride 9. Agamia NF, Abou Youssif T, El-Hadidy A, El-Abd A. Benign prostatic have been established to be efcacious for the hyperplasia, metabolic syndrome and androgenic alopecia: Is treatment of benign prostatic hyperplasia and there a possible relationship? Arab J Urol. 2016;14(2):157-62. Epub 2016/08/05. [PMID: 27489744]. androgenetic alopecia by substantially reducing the 10. Liu L, Zhao S, Li F, Li E, Kang R, Luo L, Luo J, Wan S, Zhao Z. Efect of levels of dihydrotestosterone [2, 3], it has also been 5alpha-Reductase Inhibitors on Sexual Function: A Meta-Analysis documented that they may increase the incidence of and Systematic Review of Randomized Controlled Trials. J Sex Med. 2016;13(9):1297-310. Epub 2016/08/01. [PMID: 27475241]. sexual dysfunction [10]. Decreased libido, ejaculation 11. Drake L, Hordinsky M, Fiedler V, Swinehart J, Unger WP, Cotterill PC, disorder, and impotence are among the most Thiboutot DM, Lowe N, Jacobson C, Whiting D, Stieglitz S, Kraus commonly reported drug related adverse efects [19]. SJ, Grifn EI, Weiss D, Carrington P, Genchef C, Cole GW, Pariser DM, Epstein ES, Tanaka W, Dallob A, Vandormael K, Geissler L, Erectile dysfunction, or impotence, has been cited as Waldstreicher J. The efects of fnasteride on scalp skin and serum the most common side efect in multiple studies for androgen levels in men with androgenetic alopecia. J Am Acad both fnasteride 5 mg/d and dutasteride 0.5mg/d, Dermatol. 1999;41(4):550-4. Epub 1999/09/25. [PMID: 10495374]. 12. Kiguradze T, Temps WH, Yarnold PR, Cashy J, Brannigan RE, Nardone followed by decreased libido [5, 15, 22, 25, 27, 45]. In B, Micali G, West DP, Belknap SM. Persistent erectile dysfunction the largest meta-analysis to date on 5αRIs, there was in men exposed to the 5alpha-reductase inhibitors, fnasteride, found to be a signifcantly increased risk of sexual or dutasteride. PeerJ. 2017;5:e3020. Epub 2017/03/16. [PMID: 28289563]. dysfunction (156% increase) for men being treated 13. Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, with fnasteride or dutasteride for BPH, whereas there Wilson T, Rittmaster RS. The importance of dual 5alpha-reductase was not a signifcant association for those treated for inhibition in the treatment of male pattern hair loss: results of a randomized placebo-controlled study of dutasteride versus AGA [10]. Dutasteride 0.5 mg/d has also been shown fnasteride. J Am Acad Dermatol. 2006;55(6):1014-23. Epub to have a greater incidence of adverse sexual efects 2006/11/18. [PMID: 17110217]. than fnasteride 5 mg/d in the treatment of BPH [10]. 14. Mysore V. Finasteride and sexual side efects. Indian Dermatol Online J. 2012;3(1):62-5. Epub 2012/11/07. [PMID: 23130269]. Unfortunately, there is no consensus regarding the 15. Moinpour CM, Darke AK, Donaldson GW, Thompson IM, Jr., relation between 5αRIs dosage and the likelihood of Langley C, Ankerst DP, Patrick DL, Ware JE, Jr., Ganz PA, Shumaker sexual dysfunction and further study is needed in this SA, Lippman SM, Coltman CA, Jr. Longitudinal analysis of sexual function reported by men in the Prostate Cancer Prevention Trial. area [10, 38, 55]. It is based on these fndings that we J Natl Cancer Inst. 2007;99(13):1025-35. Epub 2007/06/29. [PMID: recommend practitioners both consider and discuss 17596576]. the possible sexual side efects and risk of depression 16. Carbone DJ, Jr., Hodges S. Medical therapy for benign prostatic hyperplasia: sexual dysfunction and impact on quality of life. Int J with their patients prior to selecting a drug therapy. Impot Res. 2003;15(4):299-306. Epub 2003/08/23. [PMID: 12934061]. 17. Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford

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LG, Lieber MM, Cespedes RD, Atkins JN, Lippman SM, Carlin SM, W, Price VH, Van Neste D, Roberts JL, Hordinsky M, Shapiro J, Ryan A, Szczepanek CM, Crowley JJ, Coltman CA, Jr. The infuence Binkowitz B, Gormley GJ. Finasteride in the treatment of men of fnasteride on the development of prostate cancer. N Engl J Med. with androgenetic alopecia. Finasteride Male Pattern Hair Loss 2003;349(3):215-24. Epub 2003/06/26. [PMID: 12824459]. Study Group. J Am Acad Dermatol. 1998;39(4 Pt 1):578-89. Epub 18. Singh MK, Avram M. Persistent sexual dysfunction and depression 1998/10/20. [PMID: 9777765]. in fnasteride users for male pattern hair loss: a serious concern 31. Kawashima M, Hayashi N, Igarashi A, Kitahara H, Maeguchi M, or red herring? J Clin Aesthet Dermatol. 2014;7(12):51-5. Epub Mizuno A, Murata Y, Nogita T, Toda K, Tsuboi R, Ueki R, Yamada 2015/01/15. [PMID: 25584139]. M, Yamazaki M, Matsuda T, Natsumeda Y, Takahashi K, Harada S. 19. Traish AM, Hassani J, Guay AT, Zitzmann M, Hansen ML. Adverse Finasteride in the treatment of Japanese men with male pattern side efects of 5alpha-reductase inhibitors therapy: persistent hair loss. Eur J Dermatol. 2004;14(4):247-54. Epub 2004/08/21. diminished libido and erectile dysfunction and depression in a [PMID: 15319158]. subset of patients. J Sex Med. 2011;8(3):872-84. Epub 2010/12/24. 32. Leyden J, Dunlap F, Miller B, Winters P, Lebwohl M, Hecker D, Kraus [PMID: 21176115]. S, Baldwin H, Shalita A, Draelos Z, Markou M, Thiboutot D, Rapaport 20. Marberger MJ. Long-term efects of fnasteride in patients with M, Kang S, Kelly T, Pariser D, Webster G, Hordinsky M, Rietschel R, benign prostatic hyperplasia: a double-blind, placebo-controlled, Katz HI, Terranella L, Best S, Round E, Waldstreicher J. Finasteride multicenter study. PROWESS Study Group. Urology. 1998;51(5):677- in the treatment of men with frontal male pattern hair loss. J Am 86. Epub 1998/06/04. [PMID: 9610579]. Acad Dermatol. 1999;40(6 Pt 1):930-7. Epub 1999/06/12. [PMID: 21. McConnell JD, Bruskewitz R, Walsh P, Andriole G, Lieber M, 10365924]. Holtgrewe HL, Albertsen P, Roehrborn CG, Nickel JC, Wang DZ, 33. Van Neste D, Fuh V, Sanchez-Pedreno P, Lopez-Bran E, Wolf H, Taylor AM, Waldstreicher J. The efect of fnasteride on the risk of Whiting D, Roberts J, Kopera D, Stene JJ, Calvieri S, Tosti A, Prens acute urinary retention and the need for surgical treatment among E, Guarrera M, Kanojia P, He W, Kaufman KD. Finasteride increases men with benign prostatic hyperplasia. Finasteride Long-Term anagen hair in men with androgenetic alopecia. Br J Dermatol. Efcacy and Safety Study Group. N Engl J Med. 1998;338(9):557-63. 2000;143(4):804-10. Epub 2000/11/09. [PMID: 11069460]. Epub 1998/02/26. [PMID: 9475762]. 34. Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger 22. Fwu CW, Eggers PW, Kirkali Z, McVary KT, Burrows PK, Kusek M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall JW. Change in sexual function in men with lower urinary tract DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS. Efect symptoms/benign prostatic hyperplasia associated with long-term of dutasteride on the risk of prostate cancer. N Engl J Med. treatment with doxazosin, fnasteride and combined therapy. J 2010;362(13):1192-202. Epub 2010/04/02. [PMID: 20357281]. Urol. 2014;191(6):1828-34. Epub 2013/12/18. [PMID: 24342143]. 35. Roehrborn CG, Boyle P, Nickel JC, Hoefner K, Andriole G. Efcacy 23. O’Leary MP, Fowler FJ, Lenderking WR, Barber B, Sagnier PP, Guess and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 HA, Barry MJ. A brief male sexual function inventory for urology. (dutasteride) in men with benign prostatic hyperplasia. Urology. Urology. 1995;46(5):697-706. Epub 1995/11/01. [PMID: 7495124]. 2002;60(3):434-41. Epub 2002/09/28. [PMID: 12350480]. 24. Andersen JT, Ekman P, Wolf H, Beisland HO, Johansson JE, Kontturi 36. Traish AM, Mulgaonkar A, Giordano N. The dark side of 5alpha- M, Lehtonen T, Tveter K. Can fnasteride reverse the progress of reductase inhibitors’ therapy: sexual dysfunction, high Gleason benign prostatic hyperplasia? A two-year placebo-controlled grade prostate cancer and depression. Korean J Urol. 2014;55(6):367- study. The Scandinavian BPH Study Group. Urology. 1995;46(5):631- 79. Epub 2014/06/24. [PMID: 24955220]. 7. Epub 1995/11/01. [PMID: 7495111]. 37. Roehrborn CG, Siami P, Barkin J, Damiao R, Major-Walker K, Nandy 25. Nickel JC, Fradet Y, Boake RC, Pommerville PJ, Perreault JP, Afridi SK, I, Morrill BB, Gagnier RP, Montorsi F. The efects of combination Elhilali MM. Efcacy and safety of fnasteride therapy for benign therapy with dutasteride and tamsulosin on clinical outcomes prostatic hyperplasia: results of a 2-year randomized controlled trial in men with symptomatic benign prostatic hyperplasia: 4-year (the PROSPECT study). PROscar Safety Plus Efcacy Canadian Two results from the CombAT study. Eur Urol. 2010;57(1):123-31. Epub year Study. Can Med Assoc J. 1996;155(9):1251-9. Epub 1996/11/01. 2009/10/15. [PMID: 19825505]. [PMID: 8911291]. 38. Eun HC, Kwon OS, Yeon JH, Shin HS, Kim BY, Ro BI, Cho HK, Sim 26. Vaughan D, Imperato-McGinley J, McConnell J, Matsumoto AM, WY, Lew BL, Lee WS, Park HY, Hong SP, Ji JH. Efcacy, safety, and Bracken B, Roy J, Sullivan M, Pappas F, Cook T, Daurio C, Meehan tolerability of dutasteride 0.5 mg once daily in male patients with A, Stoner E, Waldstreicher J. Long-term (7 to 8-year) experience male pattern hair loss: a randomized, double-blind, placebo- with fnasteride in men with benign prostatic hyperplasia. Urology. controlled, phase III study. J Am Acad Dermatol. 2010;63(2):252-8. 2002;60(6):1040-4. Epub 2002/12/12. [PMID: 12475666]. Epub 2010/07/08. [PMID: 20605255]. 27. Wilton L, Pearce G, Edet E, Freemantle S, Stephens MD, Mann RD. 39. Gubelin Harcha W, Barboza Martinez J, Tsai TF, Katsuoka K, The safety of fnasteride used in benign prostatic hypertrophy: a Kawashima M, Tsuboi R, Barnes A, Ferron-Brady G, Chetty D. A non-interventional observational cohort study in 14,772 patients. randomized, active- and placebo-controlled study of the efcacy Br J Urol. 1996;78(3):379-84. Epub 1996/09/01. [PMID: 8881946]. and safety of diferent doses of dutasteride versus placebo and 28. Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh fnasteride in the treatment of male subjects with androgenetic PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS, et al. alopecia. J Am Acad Dermatol. 2014;70(3):489-98.e3. Epub The efect of fnasteride in men with benign prostatic hyperplasia. 2014/01/15. [PMID: 24411083]. The Finasteride Study Group. N Engl J Med. 1992;327(17):1185-91. 40. Kaplan SA, Chung DE, Lee RK, Scofeld S, Te AE. A 5-year Epub 1992/10/22. [PMID: 1383816]. retrospective analysis of 5alpha-reductase inhibitors in men with 29. Roberts JL, Fiedler V, Imperato-McGinley J, Whiting D, Olsen E, benign prostatic hyperplasia: fnasteride has comparable urinary Shupack J, Stough D, DeVillez R, Rietschel R, Savin R, Bergfeld W, symptom efcacy and prostate volume reduction, but less sexual Swinehart J, Funicella T, Hordinsky M, Lowe N, Katz I, Lucky A, Drake side efects and breast complications than dutasteride. Int J Clin L, Price VH, Weiss D, Whitmore E, Millikan L, Muller S, Genchef C, et Pract. 2012;66(11):1052-5. Epub 2012/10/17. [PMID: 23067029]. al. Clinical dose ranging studies with fnasteride, a type 2 5alpha- 41. Bruskewitz R, Girman CJ, Fowler J, Rigby OF, Sullivan M, Bracken reductase inhibitor, in men with male pattern hair loss. J Am Acad RB, Fusilier HA, Kozlowski D, Kantor SD, Johnson EL, Wang DZ, Dermatol. 1999;41(4):555-63. Epub 1999/09/25. [PMID: 10495375]. Waldstreicher J. Efect of fnasteride on bother and other health- 30. Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld related quality of life aspects associated with benign prostatic

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hyperplasia. PLESS Study Group. Proscar Long-term Efcacy and steroids in cerebrospinal fuid and plasma. J Steroid Biochem Mol Safety Study. Urology. 1999;54(4):670-8. Epub 1999/10/08. [PMID: Biol. 2015;146:74-9. Epub 2014/04/11. [PMID: 24717976]. 10510926]. 58. Irwig MS. Depressive symptoms and suicidal thoughts among 42. Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, former users of fnasteride with persistent sexual side efects. J Clin Herlihy R, Fitch W, Labasky R, Auerbach S, Parra R, Rajfer J, Culbertson Psychiatry. 2012;73(9):1220-3. Epub 2012/09/04. [PMID: 22939118]. J, Lee M, Bach MA, Waldstreicher J. Incidence and severity of sexual 59. Ganzer CA, Jacobs AR, Iqbal F. Persistent sexual, emotional, and adverse experiences in fnasteride and placebo-treated men with cognitive impairment post-fnasteride: a survey of men reporting benign prostatic hyperplasia. Urology. 2003;61(3):579-84. Epub symptoms. Am J Men’s Health. 2015;9(3):222-8. Epub 2014/06/15. 2003/03/18. [PMID: 12639651]. [PMID: 24928450]. 43. Macfarlane GJ, Botto H, Sagnier PP, Teillac P, Richard F, Boyle P. The 60. Ganzer CA, Jacobs AR. Emotional Consequences of Finasteride: relationship between sexual life and urinary condition in the French Fool’s Gold. Am J Men’s Health. 2016. Epub 2016/02/13. [PMID: community. J Clin Epidemiol. 1996;49(10):1171-6. Epub 1996/10/01. 26868914]. [PMID: 8826998]. 44. Irwig MS, Kolukula S. Persistent sexual side efects of fnasteride for male pattern hair loss. J Sex Med. 2011;8(6):1747-53. Epub 2011/03/23. [PMID: 21418145]. 45. Irwig MS. Persistent sexual side efects of fnasteride: could they be permanent? J Sex Med. 2012;9(11):2927-32. Epub 2012/07/14. [PMID: 22789024]. 46. Basaria S, Jasuja R, Huang G, Wharton W, Pan H, Pencina K, Li Z, Travison TG, Bhawan J, Gonthier R, Labrie F, Dury AY, Serra C, Papazian A, O’Leary M, Amr S, Storer TW, Stern E, Bhasin S. Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss. J Clin Endocrinol Metab. 2016;101(12):4669-80. Epub 2016/09/24. [PMID: 27662439]. 47. Finn DA, Beadles-Bohling AS, Beckley EH, Ford MM, Gililland KR, Gorin-Meyer RE, Wiren KM. A new look at the 5alpha-reductase inhibitor fnasteride. CNS Drug Rev. 2006;12(1):53-76. Epub 2006/07/13. [PMID: 16834758]. 48. Dubrovsky B. Neurosteroids, neuroactive steroids, and symptoms of afective disorders. Pharmacol Biochem Behav. 2006;84(4):644- 55. Epub 2006/09/12. [PMID: 16962651]. 49. Charalampopoulos I, Remboutsika E, Margioris AN, Gravanis A. Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol Metab: TEM. 2008;19(8):300-7. Epub 2008/09/06. [PMID: 18771935]. 50. Romeo E, Strohle A, Spalletta G, di Michele F, Hermann B, Holsboer F, Pasini A, Rupprecht R. Efects of antidepressant treatment on neuroactive steroids in major depression. Am J Psychiatry. 1998;155(7):910-3. Epub 1998/07/11. [PMID: 9659856]. 51. Lephart ED. Age-related changes in brain and pituitary 5 alpha- reductase with fnasteride (Proscar) treatment. Neurobiol Aging. 1995;16(4):647-50. Epub 1995/07/01. [PMID: 8544916]. 52. Welk B, McArthur E, Ordon M, Anderson KK, Hayward J, Dixon S. Association of Suicidality and Depression With 5alpha-Reductase Inhibitors. JAMA Intern Med. 2017;177(5):683-91. Epub 2017/03/21. [PMID: 28319231]. 53. Melcangi RC, Santi D, Spezzano R, Grimoldi M, Tabacchi T, Fusco ML, Diviccaro S, Giatti S, Carra G, Caruso D, Simoni M, Cavaletti G. Neuroactive steroid levels and psychiatric and andrological features in post-fnasteride patients. J Steroid Biochem Mol Biol. 2017;171:229-35. Epub 2017/04/15. [PMID: 28408350]. 54. Altomare G, Capella GL. Depression circumstantially related to the administration of fnasteride for androgenetic alopecia. J Dermatol. 2002;29(10):665-9. Epub 2002/11/16. [PMID: 12433001]. 55. Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A. Finasteride induced depression: a prospective study. BMC Clin Pharmacol. 2006;6:7. Epub 2006/10/10. [PMID: 17026771]. 56. Ali AK, Heran BS, Etminan M. Persistent Sexual Dysfunction and Suicidal Ideation in Young Men Treated with Low-Dose Finasteride: A Pharmacovigilance Study. Pharmacotherapy. 2015;35(7):687-95. Epub 2015/07/03. [PMID: 26133534]. 57. Caruso D, Abbiati F, Giatti S, Romano S, Fusco L, Cavaletti G, Melcangi RC. Patients treated for male pattern hair with fnasteride show, after discontinuation of the drug, altered levels of neuroactive

- 12 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 ACP ACP Outcome Study Grading High High High High High ------Level of Evidence Level Double-blind, random placebo-conized, study;trolled Sexual Activity Scale (0-100) assessed sexual dysfunction Double-blind, 2-year place randomized, bo-controlled, multi study center Double-blind, 4-year, place randomized, bo-controlled trial random Multicenter, double-blind,ized, placebo-controlled, clinical trial 2-year, Multicenter, double-blind, place bo-controlled study - Per sistent ects E f No No No No No - - ect (%) Side E f Placebo on Sexual Activity lower Scored sexual better indicating Scale, function ects (7%) e f Sexual adverse libido (2.8%) Decreased (0.6%) disorder Ejaculation (4.7%) Impotence libido (3.4%) Decreased (3.7%) Impotence volume ejaculate Decreased (0.8%) (0.1%) disorder Ejaculation follow-up: 1 year Baseline vs. (11%) drive sexual Worse erectile function (8%) Worse ejaculatory function Worse (6%) satisfac sexual overall Worse tion (14%) follow-up: 4 year Baseline vs. (16%) drive sexual Worse erectile function (13%) Worse ejaculatory function Worse (12%) satisfac sexual overall Worse tion (17%) Sexual dysfunction (10%)

ect (%) Side E f Activity Scale score 3.21 Sexual points higher in Finasteride arm at points higher in month 6 and 2.11 Finasteride arm at year 7 ects (10%) e f Sexual adverse libido (4%) Decreased (2.1%) disorder Ejaculation (6.6%) Impotence libido (6.4%) Decreased (8.1%) Impotence volume ejaculate Decreased (3.7%) (0.8%) disorder Ejaculation follow-up: 1 year Baseline vs. (16%) drive sexual Worse erectile function (11%) Worse ejaculatory function (9%) Worse satisfaction sexual overall Worse (15%) follow-up: 4 year Baseline vs. (22%) drive sexual Worse erectile function (18%) Worse ejaculatory function (18%) Worse satisfaction sexual overall Worse (21%) Sexual dysfunction (19%) N 17,313 3,168 2,070 1,367 707 Dosage (daily) (5mg) Finasteride (5mg) Finasteride (5mg) Finasteride (5mg) Finasteride (5mg) Finasteride Source Moinpour et al. Cancer Prostate The [15] Trial Prevention Marberger et al. PROWESS Study [20] McConnell et al. Finasteride Term Long- Effcacy and Safety Study Group [21] Fwu et al. [22] Andersen et al. Scandinavian BPH Study Group [24] ects of 5-Alpha-Reductase Inhibitors Finasteride and Dutasteride ectsf 1 Side E of 5-Alpha-Reductase Finasteride Inhibitors Table ectsf Side E Sexual

- 13 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 High Moderate Low High High - - - - - Double-blind, 2-year, Double-blind, 2-year, place randomized, bo-controlled multi study center Double-blinded, place bo-controlled study Observational cohort study 1-year, Multicenter, random double blind, placebo-control ized, study ran 1-year, Multicenter, double-blind,domized, placebo-controlled study No No No No No Ejaculation disorder (1.7%) disorder Ejaculation (6.3%) Impotence During study: 6 month (0%) Impotence libido (0%) Decreased (0%) disorder Ejaculation group N/A – No control libido (1.3%) Decreased (1.7%) disorder Ejaculation (1.7%) Impotence dysfunction (0.3%) Orgasm ects (3.4%) e f Sexual adverse libido (3%) Decreased Erectile dysfunction (0%)

st Ejaculation disorder (7.7%) disorder Ejaculation (15.8%) Impotence During study: 6 month (0.7%) Impotence libido (0.7%) Decreased (0%) disorder Ejaculation During voluntary extension 1 year: (6.4%) Impotence libido (10.9%) Decreased (5.8%) disorder Ejaculation (2.1%) Impotence Ejaculatory (2.1%) failure libido (1%) Decreased 5mg: libido (4.7%) Decreased Ejaculatory (4.4%) disorder (3.4%) Impotence dysfunction (0.7%) Orgasm 1mg: libido (6%) Decreased (4.4%) disorder Ejaculation (5%) Impotence dysfunction (0.3%) Orgasm 5mg: ects (3.6%) e f Sexual adverse libido (2.7%) Decreased Erectile dysfunction (1.8) 1mg: ects (4.3%) e f Sexual adverse libido (1.7%) Decreased Erectile dysfunction (2.6%) 472 190 14,772 893 548 Finasteride (5mg) Finasteride (5mg) Finasteride (5mg) Finasteride (5mg, Finasteride 1mg) (5mg, Finasteride 0.2mg, 1mg, 0.01mg) Nickel et al. PROSPECT Study [25] et al. [26] Vaughan Wilton et al. [27] Gormley et al. The Study Group [28] Finasteride Roberts et al. [29] ects of 5-Alpha-Reductase Inhibitors Finasteride and Dutasteride ectsf 1 Side E of 5-Alpha-Reductase Finasteride Inhibitors Table ectsf Side E Sexual

- 14 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 Moderate High High High Moderate High low Very High High ------Multicenter, dou Multicenter, ble-blind, randomized, placebo-controlled study 1-year, replicate, Two double-blind, random placebo-conized, studies trolled Double-blind, random study 48-week ized, Double-blind, 1-year, placebo-controlled, multi randomized study center dou Multicenter, ble-blind, randomized, placebo-controlled study Double-blind, 4-year, placebo-controlled study uncontrolled Two studies dou Multicenter, ran ble-blind, 4-year, placebo-condomized, study trolled Double-blind, 2-year, place randomized, bo-controlled study No No No No No Yes Yes No No Decreased libido (4.5%) Decreased Sexual function adverse (2.2%) events Erectile dysfunction (0.9%) ejaculatory Decreased vol (0.4%) libido (1.3%) Decreased libido (2.2%) Decreased ects (2%) e f Sexual adverse ects (0.9%) e f Sexual adverse (7%) events Sexual adverse Group N/A – No Control Erectile dysfunction (5.7%) libido (1.6%) Decreased (4%) Impotence libido (2.1%) Decreased (0.8%) disorder Ejaculation 5mg: libido (2.6%) Decreased 1mg: libido (0%) Decreased Sexual function adverse (4.2%) events Erectile dysfunction (1.4%) ejaculatory (1.0%) Decreased vol libido (1.9%) Decreased 1mg: libido (2.9%) Decreased 0.2mg: libido (1.5%) Decreased ects (2%) e f Sexual adverse ects (1.9%) e f Sexual adverse (15%) events Sexual adverse libido (94%) Low Erectile dysfunction (92%) (92%) arousal Decreased (69%) with orgasm Problems Erectile dysfunction (9%) libido (3.3%) Decreased (7.3%) Impotence libido (4.2%) Decreased (2.2%) disorder Ejaculation 249 1,553 414 326 212 3,040 71 6,729 4,325 Finasteride (5mg, (5mg, Finasteride 0.2mg, 1mg, 0.01mg) 0.05mg, (1mg) Finasteride (1mg Finasteride 0.2mg) vs. (1mg) Finasteride (1 mg) Finasteride (5mg) Finasteride (1mg) Finasteride Dutasteride (0.5mg) Dutasteride (0.5mg) Drake et al. [11] Drake et al. [11] Kaufman et al. The Male Pattern Finasteride Loss Study [30] Hair Kawashima et [31] al. Leyden et al. [32] Neste et al. [33] Van et al. Wessells PLESS trial [42] Irwig et al. [45], [46] Andriole et al. REDUCE trial [34] Roehrborn et al. [35] ects of 5-Alpha-Reductase Inhibitors Finasteride and Dutasteride ectsf 1 Side E of 5-Alpha-Reductase Finasteride Inhibitors Table ectsf Side E Sexual

- 15 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 High Moderate Moderate - - - - - Double-blind, random placebo-conized, trial trolled dou Multicenter, ble-blind, randomized, placebo-controlled phase III trial dou Randomized, ble-blind, placebo-con study trolled No No No Erectile dysfunction (5%) libido (2%) Decreased (4%) events Sexual adverse Sexual dysfunction (2.7%) Erectile dysfunction (1.3%) (1.3%) disorder Ejaculation Erectile dysfunction (0%) libido (0%) Decreased Erectile dysfunction (7%) libido (3%) Decreased (4.1%) events Sexual adverse Sexual dysfunction (4.1%) Erectile dysfunction (0%) (0%) disorder Ejaculation Erectile dysfunction (4%) libido (0%) Decreased 3,234 148 136 Dutasteride (0.5mg) Dutasteride (0.5mg) Dutasteride (0.5mg) Roehrborn et al. trial [37] CombAT Eun et al. [38] et al. [6] Tsukamoto ects of 5-Alpha-Reductase Inhibitors Finasteride and Dutasteride ectsf 1 Side E of 5-Alpha-Reductase Finasteride Inhibitors Table ectsf Side E Sexual

- 16 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 - ACP ACP Out come Study Grading High High High High - - - - Level of Evidence Level random Multicenter, double-blind,ized, placebo-controlled study random Multicenter, double-blinded,ized, study 29 week random Multicenter, placebo-conized, study trolled 5-year Retrospective study - Per sistent ects E f No No No No ect (%) Side E f Placebo N/A libido (1.7%) Altered (3.9%) Impotence disorders Ejaculation (3.3%) libido (3%) Decreased disorders Ejaculation (0%) (5%) Impotence N/A ect(%) Dutasteride Side E f (7%) Impotence libido (5%) Decreased (1%) disorders Ejaculation Dutasteride (0.5mg): libido (4.9%) Altered (5.4%) Impotence disorders Ejaculation (3.3%) Dutasteride (2.5mg): libido (13%) Decreased (1%) disorders Ejaculation (0%) Impotence Dutasteride (0.5mg): libido (1%) Decreased (1%) disorders Ejaculation (0%) Impotence Erectile dysfunction (5.1%) Ejaculatory dysfunction (2.4%) libido (2.7%) Decreased ect Side E f (%) Finasteride (8%) Impotence libido (6%) Decreased (1%) disorders Ejaculation (1mg): Finasteride libido (6.7%) Altered (6.1%) Impotence disorders Ejaculation (3.9%) (5mg) Finasteride libido (4%) Decreased (3%) disorders Ejaculation (1%) Impotence Erectile dysfunction (2.1%) Ejaculatory dysfunction (1.8%) libido (1.4%) Decreased N 3,160 917 416 378 Dosage (daily) Finasteride (5mg) vs. Dutasteride (0.5mg) Finasteride (1mg) vs. Dutasteride (0.02mg, 0.5mg) 0.1mg, Finasteride (5mg) vs. Dutasteride (0.05mg, 0.5mg, 0.1mg, 2.5mg) Finasteride (5mg) vs. Dutasteride (0.5mg) Source Andriole et al. [5] Gubelin Harcha et al. [39] Olsen et [13] al. Kaplan et al. [40] ects of 5-Alpha-Reductase Inhibitors Finasteride vs. Dutasteride vs. ectsf 2 Side E of 5-Alpha-Reductase Finasteride Inhibitors Table ectsf Side E Sexual

- 17 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 - - ACP ACP Outcome Study Grading High High High Moder ate Moder ate Low Low low Very - - - Level of Evidence Level Retrospective, matched cohort study longi prospective, Multicenter, clinical trial case control tudinal, placebo-conRetrospective, study trolled Retrospective pharmacovigilance disproportionality analysis Case-control study self-administered question Two naires Self-administered questionnaire Self-administered questionnaire - Per sistent Effects No Yes Yes No Yes Yes ect (%) Side E f Placebo Suicide (0.04%) Self-harm (0.14%) Depression (1.37%) Used for normal CSF and plasma neuroactive steroid levels Sexual desire (29.5 on MSHQ) – No Control Group N/A neuroactive steroid Different profle compared to cases – No Control Group N/A (10%) symptoms Depression Suicidal thoughts (3%) – No Control Group N/A - - ect (%) Side E f Suicide (0.04%) Self-harm (0.18%) (1.95%) Depression Abnormal CSF and plasma neuroac (0.88%) steroids tive Major depression (50%) Pudendal neuropathy (25%) (17 on MSHQ) Sexual desire Sexual dysfunction (11.8%) (0.79%) Suicidal ideation dys and sexual Suicidal ideation function (0.69%) f le pro steroid neuroactive erent Di f to in CSF and plasma compared controls increased score HADS-Depression 0.57 pts 0.69 increased score BDI-Depression pts of libido (9.4%) Loss dysfunction had sexual All post treatment f nasteride (75%) symptoms Depression (44%) Suicidal thoughts (93%) drive sex Decreased (40%) impotence Complete erectile dysfunctionIntermittent (83%) ect (73%) a f Depressed (63%) Suicidal ideations Dosage (daily) 186,394 41 56 4,910 19 128 61 131 - N Finas teride or Dutasteride Finasteride (1 mg- 1.25mg) Finasteride (1mg) Finasteride (1mg) Finasteride (1mg- 1.25mg) Finasteride (1mg) Finasteride (1mg) Finasteride (1mg)

Source [55] et al. Welk Melcangi et al. [57] Basaria et al. [47] Ali [60] et al. Caruso et al. [61] Rahimi- Ardabili et al. [59] [62] al. et Irwig Ganzer et al. [63] ectsf 3 Side E of 5-Alpha-Reductase Inhibitors Table ectsf Side E Depressive

- 18 - Volume 23 Number 11 | November 2017 Dermatology Online Journal || Review DOJ 23 (11): 3 Very low Very low Very Self-administered questionnaire Retrospective case series of 19 subjects that developed moderate to severe depression on fnasteride therapy Yes No N/A – No Control Group N/A Group N/A – No Control Moderate to severe depression depression severe to Moderate (39%) (5%) Extreme depression anxiety (16%) Moderate Sexual (21%) disturbances 97 19 Finasteride (1mg) Finasteride (1mg) Ganzer et al. [64] al. et Altomare [58] ectsf 3 Side E of 5-Alpha-Reductase Inhibitors Table ectsf Side E Depressive

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